Qiwen Pang†
Xin Xie
Xiang Li
Bo Han- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy and College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
Bicyclo[1.1.1]pentylamines (BPCAs), emerging as sp3-rich surrogates for aniline and its derivatives, demonstrate unique structural features and physicochemical profiles in medicinal and synthetic chemistry. In recent years, compared with conventional synthetic approaches, the rapid development of radical chemistry enables the assembly of valuable bicyclo[1.1.1]pentylamines scaffold directly through the amination transformation of highly strained [1.1.1]propellane. In this review, we concisely summarize the emerging role of radical chemistry in the construction of BCPAs motif, highlighting two different and powerful radical-involved strategies including C-centered and N-centered radical pathways under appropriate conditions. The future direction concerning BCPAs is also discussed at the end of this review, which aims to provide some inspiration for the research of this promising project.
Introduction
As one of the primary and versatile materials, aniline moved to the center of the stage in the history of the chemical industry in 1856 due to the synthesis of the first artificial dye called mauveine by British chemist William Henry Perkin (Scheme 1A, left) (Perkin, 1896). Despite the significance of aniline utilized as an essential chemical in the dye industry and industrial production of rubber chemicals and 4,4′-diphenylmethane diisocyanate (MDI) (North, 2005), the remarkable progress has also been witnessed in the discovery of novel medicine and powerful pesticide. As a valuable and common structural element, aniline and its derivatives widely exist in various bioactive natural products, pharmaceuticals, clinical drugs, and pesticides (Scheme 1A, right) (Lacroix et al., 1999; Gan et al., 2013; Greig and Garnock-Jones, 2016; Desideri et al., 2019). According to the statistics supported by the University of Arizona, approximately 54% and 65% of top 200 small molecule pharmaceuticals by retail sales in 2020 and 2021, respectively, contain at least an aniline unit (McGrath et al., 2010).
Scheme 1. Advancements of BCPAs in the medicinal and synthetic chemistry.
With the rise of green chemistry and precision therapy, the pursuit of targeted drugs featuring excellent tissue and cell selectivity (Wang et al., 2020; Chu et al., 2021; Sun et al., 2021), high efficiency, and the environment-friendly synthetic procedure (Peng et al., 2019; Zuo et al., 2021) has increasingly become a research trend in medicinal (Friedman et al., 2015; Soto et al., 2020; Manzari et al., 2021; Mitchell et al., 2021) and synthetic chemistry (Dunn, 2012; Simon and Li, 2012; Galuszka et al., 2013; Newman and Jensen, 2013; Jahangirian et al., 2017; Rogers and Jensen, 2019). These concepts put higher requirements on the metabolic tolerance (Arnott and Planey, 2012; Wishart, 2016; Quinn et al., 2017; Yang et al., 2019; Bi et al., 2020), pharmacokinetic properties (Ferreira and Andricopulo, 2019; Yang et al., 2019; Jia et al., 2020), and synthetic process of new drugs (Nadin et al., 2012; Gerry and Schreiber, 2018; Campos et al., 2019; Lenci and Trabocchi, 2020; Han et al., 2021). Although aniline and its derivatives have become a prevalent substructure in discovering new drugs, their propensity for reactive metabolite (RM) formation triggered by cytochrome P450 (CYP450)-mediated oxidation may cause drug−drug interactions or adverse drug interactions (Scheme 1B, left) (Stepan et al., 2011; Orr et al., 2012; Kalgutkar, 2015). As a result, in some cases, aniline unit(s) incorporated into the structure of drug candidates cannot fulfill the high standard mentioned above. One of the most typical cases is the structural optimization of the Hsp 90 inhibitor due to the resistance towards metabolic clearance caused by benzamide moiety (Scheme 1B, right) (Zehnder et al., 2008; Zehnder et al., 2011). Hence, developing a strategic replacement of the aniline unit(s) to address these challenges is highly demanded.
In modern drug discovery, installing a three-dimensional small-ring framework into the structure of drug candidates provides unique opportunities to expand potential drug-like chemical space and alert the physicochemical profiles while maintaining comparable levels of bioactivity (Carreira and Fessard, 2014; Auberson et al., 2017; Measom et al., 2017). The bicyclo[1.1.1]pentanes (BCPs) have recently received considerable attention from the pharmaceutical, agrochemical, and materials industries. It has have become established as useful sp3-rich surrogates for arenes (Stepan et al., 2012; Mykhailiuk, 2019), tert-butyl groups (Westphal et al., 2015), and alkynes functional groups (Makarov et al., 2017). As the potential nontoxic bioisosteres for aniline and N-tert-butyl moieties, bicyclo[1.1.1]pentylamines (BCPAs) offer straightforward access to improve medicinal properties in drug candidates (Lovering et al., 2009). In particularly, the BCPAs motif demonstrates significant interest in circumventing the deleterious metabolic processes of an aniline moiety because of its higher Fsp3 and three-dimensionality, and its spatial approximation to aniline in physical parameters (Scheme 1B) (Walsh and Miwa, 2011; Kalgutkar, 2015; Sodano et al., 2020). Indeed, this strategic replacement has been successfully applied to optimize the metabolic level of the Hsp 90 inhibitor developed by Pfizer Company (Scheme 1B, right) (Zehnder et al., 2008; Zehnder et al., 2011). Recognizing the critical value of BCPAs scaffold, tremendous efforts from the scientific community have been increasingly devoted to efficiently constructing BCPAs scaffold over the past decades (Sodano et al., 2020).
From the retrosynthesis point of view, BCPAs can be smoothly and (in)directly produced by amination functionalization of the highly strained [1.1.1]propellane at the bridgehead position (Wiberg and Waddell, 1990; Milligan and Wipf, 2016; Sterling et al., 2020), where the internal central C-C bond can be readily cleaved under a strain-release approach (Gianatassio et al., 2016; Lopchuk et al., 2017). And the [1.1.1]propellane can be easily obtained by intramolecular reductive coupling reaction of 1,3-dibromobicyclo[1.1.1]pentane firstly reported by Wiberg and Walker in 1982, and later by using 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane as starting material developed by Szeimies and co-workers (Scheme 1C, left) (Wiberg and Walker, 1982; Semmler et al., 1985). Early approaches to BCPAs involved multistep routes utilizing preformed BCP building blocks derived from a strained [1.1.1]propellane, such as acyl nitrene rearrangements or reduction of BCP azides or hydrazines (Scheme 1C, I–III) (Wiberg and Waddell, 1990; Bunker et al., 2011; Goh et al., 2014). In 2006, the breakthrough was made by Baran et al., who developed the strain-release amination of [1.1.1]propellane leading to access to monosubstituted BCPAs (Scheme 1C, IV) (Gianatassio et al., 2016; Lopchuk et al., 2017). Then, the Gleason group extended this approach to synthesizing 1,3-disubstituted BCPAs (Scheme 1C, IV) (Hughes et al., 2019). However, these processes require elevated temperatures, restricting functional group tolerance.
In recent years, fast and impressive achievements have been witnessed in radical chemistry, and several approaches for constructing BCPAs have been continuously established (Chen et al., 2016; Oberg, 2016; Studer and Curran, 2016; Yu et al., 2020; Parsaee et al., 2021; Sumida and Ohmiya, 2021; Chan et al., 2022; Holmberg-Douglas and Nicewicz, 2022). On the one hand, adding C-centered radicals [generated under Fe(II) or metalaphotoredox catalysis] to [1.1.1]propellane offers alternative solutions for synthesizing BCPAs in a rapid and reaction manner (Scheme 1C, V–VI) (Kanazawa et al., 2017; Zhang et al., 2020). On the other hand, in contrast to the amination of BCPAs formed by the addition of C-centered radicals, reactions with the direct addition of N-centered radicals to [1.1.1]propellane seem like a concise and promising approach to BCPAs frameworks. However, this strategy lay dormant for more than 30 years after the seminal work of Wiberg on the reaction of BCP with nitric oxide (Wiberg and Waddell, 1990). At present, the addition of N-centered radicals (promoted by boron catalysis, metalaphotoredox catalysis, or electron donor-acceptor (EDA) complex) to [1.1.1]propellane for the build-up of BCPAs has been established by limited individual groups (Scheme 1C, VII–IX) (Kim et al., 2020; Pickford et al., 2021; Shin et al., 2021). Nonetheless, the challenge of narrow substrate scopes and limited N-centered radical species remains unsolved. Considering the great potential of this valuable motif in synthetic and medicinal chemistry, sufficient attention from the scientific community should be paid to this promising motif.
Although several essential reviews focusing on constructing BCP derivatives have recently been published (He et al., 2020; Anderson et al., 2021), the advancement of radical chemistry in synthesizing BCPAs still lacks a concise review in this fast-growing and exciting field (Yu and Shi, 2022). In this review, we concisely summarize the fast-growing development of radical chemistry in the assembly of BCPAs motif, highlighting two different and powerful radical-involved strategies triggering the cleavage of the central bond of [1.1.1]propellane. The future direction concerning BCPAs is also discussed at the end of this review, which aims to provide some inspiration for the research of this promising project.
Amination strategies to bicyclo[1.1.1]pentylamines
Amination triggered by C-centered radicals
In 2019, Uchiyama’s group developed the first radical multicomponent carboamination of [1.1.1]propellane to synthesize multi-functionalized BCPA derivatives (Scheme 2, left) (Kanazawa et al., 2017). With the aid of density functional theory (DFT) calculations, it was found that di-tert-butyl azodicarboxylate 2, as the free radical receptor of 3-substituted BCP-radical (INT 1), can produce more stable free radical intermediates (INT 2). This chemical property of the substrate can avoid the self-polymerization of 1 over the reaction process and make the effective free radical chain reaction possible. After optimizing the conditions of free radical multicomponent reaction, the optimal conditions were determined with iron(II) phthalocyanine [Fe(Pc)] as a catalyst, tert-butyl hydroperoxide (TBHP) as oxidant, and Cs2CO3 as additive. Finally, under the condition of a tin-free/photoirradiation-free system, a series of novel multi-functionalized bicyclo[1.1.1]pentane derivatives were synthesized in one-pot operation with a yield of 38%–72%.
Scheme 2. Approaches of C-centered radicals to valuable BCPAs.
Although the above scheme proves the feasibility of the single-step carboamination multicomponent reaction via radical addition, the applicability of the reaction is still limited because only hydrazine is used as the free radical precursor. In 2019, McMillan and his research team made a breakthrough in this field (Scheme 2, right) (Zhang et al., 2020). Using various free radical precursors 5 and heteroatom nucleophiles 6, they prepared a series of different functionalized dicyclopentanes with good yields through metal photo-oxidation-reduction catalytic reactions. Based on the importance of copper catalyst to the reaction system, the author first investigated copper salts and ligands and found that diketonate ligands such as acetylacetonate (acac) can effectively form the required three-component products, thus effectively avoiding the occurrence of free radical side reactions. Mechanistic investigation showed that the alkyl radical intermediates were generated under the catalytic cycle of the photocatalyst Ir(ppy)3. Subsequently, the nucleophile-ligated copper complex captured the BCP radical generated by radical addition. Eventually, the target product was obtained by reductive elimination.
Amination triggered by N-centered radicals
Compared to C-centered radicals, the direct use of N-centered radicals to construct disubstituted BCPAs would be a more challenging path due to the susceptibility of nitrogen radicals to background reactions such as hydrogen extraction (Suarez et al., 2013; Xiong and Zhang, 2016; Kwon et al., 2022). In 2020, Leonori’s team reported the divergent strain-release amino-functionalization of [1.1.1]propellane with electrophilic nitrogen radicals for the first time (Scheme 3, left) (Kim et al., 2020). Based on the team’s previous research work, they hypothesized that under visible light excitation, the photocatalyst would be able to oxidize the carboxylic acid functional group of the free radical precursor 8, triggering the extrusion of carbon dioxide and acetone and form the amide radical INT 4. Then, by using the electrophilic property of the species, the electron-rich 1 was successfully intercepted, the free radical strain release amination was realized, and the BCPA radical INT5. Finally, the species provides a variety of target components 10 through atom/group transfer reactions (SH2) with a series of SOMOphiles (X-Y) 9. In terms of substrate adaptability, to meet the kinetic priority of the final atom/group transfer step over BCP radical oligomerization, they combined with density functional calculation to avoid side reactions. They found that six different pro-SOMOs were compatible, which supported the construction of various target products. This method dramatically expands the range of substituted BCPA obtained by free radical addition and may be further extended to other electrophilic free radicals.
Scheme 3. Approaches of N-centered radicals to construct valuable BCPAs.
Recently, the strategy of electron donor-acceptor (EDA) complexes has been widely explored to drive a new visible-light-induced conversion mode without an external photocatalyst (Rosokha and Kochi, 2008; Crisenza et al., 2020). In 2021, Hong’s team successfully provided BCPA through N-center free radicals based on this strategy (Scheme 3, right) (Shin et al., 2021). This strategy involves the photoactive formation of EDA complexes between N-aminopyridine salts 11 and acetate anions, thereby generating electrophilic amino radicals INT6. This radical cleaves the centrals bond and provides BCP radical intermediate INT7. After that, BCP radical INT7 is ready to be added to the C4 position of another N-aminopyridine salt. Next, the resulting cationic radical species INT8 undergoes deprotonation and cleavages N-N bond to get the final product 12 and amidyl radical INT6. This method directly introduces amide and pyridyl functions on the BCP core. In addition, it can also be extended to P and CF3 radicals, which have a good range of substrates.
In the same year, Anderson’s research group reported a twofold radical functionalization strategy, which provides a general and convenient new way to prepare 1,3-disubstituted iodo-BCPs (Scheme 4) (Pickford et al., 2021). In this method, N-centered radicals were obtained by fragmentation of α-iodoaziridines, which reacted with free radical receptor 1 to form a BCP radical, and then an iodine atom was extracted from the starting material of iodoazacyclopropane. These products can be further obtained by photoredox catalyzed Giese type reaction to obtain C-substituted BCPA. Interestingly, Anderson and his team succeeded in carrying out the ATRA/Giese process in a single reaction, and the overall yield of the transformation was consistent with the isolated steps.
Scheme 4. Approach of N-centered radical to construct valuable BCPAs.
Conclusion
Due to its unique structural features and physicochemical profiles in medicinal and synthetic chemistry for introducing a three-dimensional cyclic moiety into small molecules or drug candidates, BCPAs scaffold, emerging as sp3-rich surrogates for aniline and its derivatives, have recently received increasing attention from the scientific community and industries. Overall, two different approaches for synthesizing BCPAs have been developed, mainly including adding C-centered or N-centered radicals to [1.1.1]propellane, respectively. Although fast-growing achievements in this field have been witnessed over the past years, compared with remarkable advancements in the construction of BCP frameworks, sufficient attention has not been paid to the construction of these valuable BCPAs frameworks, which is anticipated to be further explored soon. For instance, the current synthesis of BCPAs depends on limited radical species of C-centered or N-centered radicals; enriching the chemical tools of radical chemistry, such as flow chemistry or electrochemistry, could provide concise access to multifunctional BCPAs (Wegner et al., 2012; Elliott et al., 2014; Porta et al., 2016; Zhao and Xia, 2018; Donnelly and Baumann, 2021). Besides, discovering new reactivity with [1.1.1]propellane at the bridgehead position under a strain-release approach could offer an alternative solution for the amination functionalization of BCP molecules. Moreover, the asymmetric catalytic synthesis of optically pure BCPA derivatives has not been achieved; novel strategies and power catalysts are highly demanded to broaden the application range and explore the potential reactivity of [1.1.1]propellane (Meggers, 2015; Dilmac et al., 2017; Wong et al., 2019). Notably, the bio-evaluation of desirable BCPAs for new drug discovery and research goes far behind its synthetic chemistry (Bauer et al., 2021). Further medicinal research on those valuable compounds should soon be devoted to this field. We believe that further development of radical chemistry methods will significantly accelerate advances in synthesizing BCPAs and their application in drug discovery.
Author contributions
QP, XL, and BH contributed to the conception and design of the study. QP, YL, JT, and QL collected the articles and performed the statistical analysis, QP, XL, and XX wrote the first draft of the manuscript. CP and BH contributed to the manuscript revision. All authors read and approved the submitted version.
Funding
We are grateful for the financial support by National Natural Science Foundation of China (Grant Nos. 82073998 and 82104376); the Science & Technology Department of Sichuan Province (Grant No. 2022JDRC0045 and 2022NSFSC0626); Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (Grant No. ZYYCXTD-D-202209) and Xinglin Scholar Research Promotion Project of Chengdu University of TCM.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
Anderson, J. M., Measom, N. D., Murphy, J. A., and Poole, D. L. (2021). Bridge functionalisation of bicyclo 1.1.1 pentane derivatives. Angew. Chem. Int. Ed. 60 (47), 24754–24769. doi:10.1002/anie.202106352
Arnott, J. A., and Planey, S. L. (2012). The influence of lipophilicity in drug discovery and design. Expert Opin. Drug Discov. 7 (10), 863–875. doi:10.1517/17460441.2012.714363
Auberson, Y. P., Brocklehurst, C., Furegati, M., Fessard, T. C., Koch, G., Decker, A., et al. (2017). Improving nonspecific binding and solubility: Bicycloalkyl groups and cubanes as para-phenyl bioisosteres. Chemmedchem 12 (8), 590–598. doi:10.1002/cmdc.201700082
Bauer, M. R., Di Fruscia, P., Lucas, S. C. C., Michaelides, I. N., Nelson, J. E., Storer, R. I., et al. (2021). Put a ring on it: Application of small aliphatic rings in medicinal chemistry. RSC Med. Chem. 12 (4), 448–471. doi:10.1039/D0MD00370K
Bi, J. F., Chowdhry, S., Wu, S. H., Zhang, W. J., Masui, K., and Mischel, P. S. (2020). Altered cellular metabolism in gliomas - an emerging landscape of actionable co-dependency targets. Nat. Rev. Cancer 20 (1), 57–70. doi:10.1038/s41568-019-0226-5
Bunker, K. D., Sach, N. W., Huang, Q., and Richardson, P. F. (2011). Scalable synthesis of 1-bicyclo[1.1.1]pentylamine via a hydrohydrazination reaction. Org. Lett. 13 (17), 4746–4748. doi:10.1021/ol201883z
Campos, K. R., Coleman, P. J., Alvarez, J. C., Dreher, S. D., Garbaccio, R. M., Terrett, N. K., et al. (2019). The importance of synthetic chemistry in the pharmaceutical industry. Science 363 (6424), eaat0805. doi:10.1126/science.aat0805
Carreira, E. M., and Fessard, T. C. (2014). Four-membered ring-containing spirocycles: Synthetic strategies and opportunities. Chem. Rev. 114 (16), 8257–8322. doi:10.1021/cr500127b
Chan, A. Y., Perry, I. B., Bissonnette, N. B., Buksh, B. F., Edwards, G. A., Frye, L. I., et al. (2022). Metallaphotoredox: The merger of photoredox and transition metal catalysis. Chem. Rev. 122 (2), 1485–1542. doi:10.1021/acs.chemrev.1c00383
Chen, J. R., Hu, X. Q., Lu, L. Q., and Xiao, W. J. (2016). Visible light photoredox-controlled reactions of N-radicals and radical ions. Chem. Soc. Rev. 45 (8), 2044–2056. doi:10.1039/c5cs00655d
Chu, X., Bu, Y., and Yang, X. (2021). Recent research progress of chiral small molecular antitumor-targeted drugs approved by the FDA from 2011 to 2019. Front. Oncol. 11, 785855. doi:10.3389/fonc.2021.785855
Crisenza, G. E. M., Mazzarella, D., and Melchiorre, P. (2020). Synthetic methods driven by the photoactivity of electron donor–acceptor complexes. J. Am. Chem. Soc. 142 (12), 5461–5476. doi:10.1021/jacs.0c01416
Desideri, N., Fioravanti, R., Proietti Monaco, L., Atzori, E. M., Carta, A., Delogu, I., et al. (2019). Design, synthesis, antiviral evaluation, and SAR studies of new 1-(phenylsulfonyl)-1H-Pyrazol-4-yl-Methylaniline derivatives. Front. Chem. 7, 214. doi:10.3389/fchem.2019.00214
Dilmac, A. M., Spuling, E., de Meijere, A., and Brase, S. (2017). Propellanes-from a chemical curiosity to "explosive" materials and natural products. Angew. Chem. Int. Ed. 56 (21), 5684–5718. doi:10.1002/anie.201603951
Donnelly, K., and Baumann, M. (2021). A continuous flow synthesis of [1.1.1]propellane and bicyclo[1.1.1]pentane derivatives. Chem. Commun. 57 (23), 2871–2874. doi:10.1039/d0cc08124h
Dunn, P. J. (2012). The importance of green chemistry in process research and development. Chem. Soc. Rev. 41 (4), 1452–1461. doi:10.1039/c1cs15041c
Elliott, L. D., Knowles, J. P., Koovits, P. J., Maskill, K. G., Ralph, M. J., Lejeune, G., et al. (2014). Batch versus flow photochemistry: A revealing comparison of yield and productivity. Chem. Eur. J. 20 (46), 15226–15232. doi:10.1002/chem.201404347
Ferreira, L. L. G., and Andricopulo, A. D. (2019). ADMET modeling approaches in drug discovery. Drug Discov. Today 24 (5), 1157–1165. doi:10.1016/j.drudis.2019.03.015
Friedman, A. A., Letai, A., Fisher, D. E., and Flaherty, K. T. (2015). Precision medicine for cancer with next-generation functional diagnostics. Nat. Rev. Cancer 15 (12), 747–756. doi:10.1038/nrc4015
Galuszka, A., Migaszewski, Z., and Namiesnik, J. (2013). The 12 principles of green analytical chemistry and the SIGNIFICANCE mnemonic of green analytical practices. TrAC Trends Anal. Chem. 50, 78–84. doi:10.1016/j.trac.2013.04.010
Gan, X. H., Zhao, C., Liang, Z. Y., Gong, X. J., Chen, H. G., and Zhou, X. (2013). Antitussive constituents of Disporum cantoniense. China J. China Mat. Med. 38 (23), 4099–4103.
Gerry, C. J., and Schreiber, S. L. (2018). Chemical probes and drug leads from advances in synthetic planning and methodology. Nat. Rev. Drug Discov. 17 (5), 333–352. doi:10.1038/nrd.2018.53
Gianatassio, R., Lopchuk, J. M., Wang, J., Pan, C. M., Malins, L. R., Prieto, L., et al. (2016). Strain-release amination. Science 351 (6270), 241–246. doi:10.1126/science.aad6252
Goh, Y. L., Tam, E. K. W., Bernardo, P. H., Cheong, C. B., Johannes, C. W., William, A. D., et al. (2014). A new route to bicyclo[1.1.1]pentan-1-amine from 1-Azido-3-iodobicyclo[1.1.1]pentane. Org. Lett. 16 (7), 1884–1887. doi:10.1021/ol500635p
Greig, S. L., and Garnock-Jones, K. P. (2016). Apixaban: A review in venous thromboembolism. Drugs 76 (15), 1493–1504. doi:10.1007/s40265-016-0644-6
Han, B., He, X. H., Liu, Y. Q., He, G., Peng, C., and Li, J. L. (2021). Asymmetric organocatalysis: An enabling technology for medicinal chemistry. Chem. Soc. Rev. 50 (3), 1522–1586. doi:10.1039/d0cs00196a
He, F. S., Xie, S. M., Yao, Y. F., and Wu, J. (2020). Recent advances in the applications of 1.1.1 propellane in organic synthesis. Chin. Chem. Lett. 31 (12), 3065–3072. doi:10.1016/j.cclet.2020.04.023
Holmberg-Douglas, N., and Nicewicz, D. A. (2022). Photoredox-catalyzed C-H functionalization reactions. Chem. Rev. 122 (2), 1925–2016. doi:10.1021/acs.chemrev.1c00311
Hughes, J. M. E., Scarlata, D. A., Chen, A. C., Burch, J. D., and Gleason, J. L. (2019). Aminoalkylation of [1.1.1]Propellane enables direct access to high-value 3-Alkylbicyclo[1.1.1]pentan-1-amines. Org. Lett. 21 (17), 6800–6804. doi:10.1021/acs.orglett.9b02426
Jahangirian, H., Lemraski, E. G., Webster, T. J., Rafiee-Moghaddam, R., and Abdollahi, Y. (2017). A review of drug delivery systems based on nanotechnology and green chemistry: Green nanomedicine. Int. J. Nanomedicine 12, 2957–2978. doi:10.2147/ijn.s127683
Jia, C. Y., Li, J. Y., Hao, G. F., and Yang, G. F. (2020). A drug-likeness toolbox facilitates ADMET study in drug discovery. Drug Discov. Today 25 (1), 248–258. doi:10.1016/j.drudis.2019.10.014
Kalgutkar, A. S. (2015). Should the incorporation of structural alerts be restricted in drug design? An analysis of structure-toxicity trends with aniline-based drugs. Curr. Med. Chem. 22 (4), 438–464. doi:10.2174/0929867321666141112122118
Kanazawa, J., Maeda, K., and Uchiyama, M. (2017). Radical multicomponent carboamination of [1.1.1]Propellane. J. Am. Chem. Soc. 139 (49), 17791–17794. doi:10.1021/jacs.7b11865
Kim, J. H., Ruffoni, A., Al-Faiyz, Y. S. S., Sheikh, N. S., and Leonori, D. (2020). Divergent strain-release amino-functionalization of [1.1.1]Propellane with electrophilic nitrogen-radicals. Angew. Chem. Int. Ed. 59 (21), 8225–8231. doi:10.1002/anie.202000140
Kwon, K., Simons, R. T., Nandakumar, M., and Roizen, J. L. (2022). Strategies to generate nitrogen-centered radicals that may rely on photoredox catalysis: Development in reaction methodology and applications in organic synthesis. Chem. Rev. 122 (2), 2353–2428. doi:10.1021/acs.chemrev.1c00444
Lacroix, G., Peignier, R., Pepin, R., Bascou, J. P., Perez, J., and Schmitz, C. (1999). Fungicidal 2-imidazolin-5-ones and 2-imidazoline-5-thiones. US5637729 (A).
Lenci, E., and Trabocchi, A. (2020). Peptidomimetic toolbox for drug discovery. Chem. Soc. Rev. 49 (11), 3262–3277. doi:10.1039/d0cs00102c
Lopchuk, J. M., Fjelbye, K., Kawamata, Y., Malins, L. R., Pan, C. M., Gianatassio, R., et al. (2017). Strain-release heteroatom functionalization: Development, scope, and stereospecificity. J. Am. Chem. Soc. 139 (8), 3209–3226. doi:10.1021/jacs.6b13229
Lovering, F., Bikker, J., and Humblet, C. (2009). Escape from flatland: Increasing saturation as an approach to improving clinical success. J. Med. Chem. 52 (21), 6752–6756. doi:10.1021/jm901241e
Makarov, I. S., Brocklehurst, C. E., Karaghiosoff, K., Koch, G., and Knochel, P. (2017). Synthesis of bicyclo 1.1.1 pentane bioisosteres of internal alkynes and para-disubstituted benzenes from 1.1.1 propellane. Angew. Chem. Int. Ed. 56 (41), 12774–12777. doi:10.1002/anie.201706799
Manzari, M. T., Shamay, Y., Kiguchi, H., Rosen, N., Scaltriti, M., and Heller, D. A. (2021). Targeted drug delivery strategies for precision medicines. Nat. Rev. Mat. 6 (4), 351–370. doi:10.1038/s41578-020-00269-6
McGrath, N. A., Brichacek, M., and Njardarson, J. T. (2010). A graphical journey of innovative organic architectures that have improved our lives. J. Chem. Educ. 87 (12), 1348–1349. doi:10.1021/ed1003806
Measom, N. D., Down, K. D., Hirst, D. J., Jamieson, C., Manas, E. S., Patel, V. K., et al. (2017). Investigation of a bicyclo[1.1.1]pentane as a phenyl replacement within an LpPLA2 inhibitor. ACS Med. Chem. Lett. 8 (1), 43–48. doi:10.1021/acsmedchemlett.6b00281
Meggers, E. (2015). Asymmetric catalysis activated by visible light. Chem. Commun. 51 (16), 3290–3301. doi:10.1039/C4CC09268F
Milligan, J. A., and Wipf, P. (2016). Straining to react. Nat. Chem. 8 (4), 296–297. doi:10.1038/nchem.2485
Mitchell, M. J., Billingsley, M. M., Haley, R. M., Wechsler, M. E., Peppas, N. A., and Langer, R. (2021). Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 20 (2), 101–124. doi:10.1038/s41573-020-0090-8
Mykhailiuk, P. K. (2019). Saturated bioisosteres of benzene: Where to go next? Org. Biomol. Chem. 17 (11), 2839–2849. doi:10.1039/c8ob02812e
Nadin, A., Hattotuwagama, C., and Churcher, I. (2012). Lead-Oriented synthesis: A new opportunity for synthetic chemistry. Angew. Chem. Int. Ed. 51 (5), 1114–1122. doi:10.1002/anie.201105840
Newman, S. G., and Jensen, K. F. (2013). The role of flow in green chemistry and engineering. Green Chem. 15 (6), 1456–1472. doi:10.1039/c3gc40374b
North, M. (2005). Amines. Synthesis, properties and applications. By stephen A lawrence. Angew. Chem. Int. Ed. 44 (14), 2053–2055. doi:10.1002/anie.200385269
Oberg, K. I. (2016). Photochemistry and astrochemistry: Photochemical pathways to interstellar complex organic molecules. Chem. Rev. 116 (17), 9631–9663. doi:10.1021/acs.chemrev.5b00694
Orr, S. T. M., Ripp, S. L., Ballard, T. E., Henderson, J. L., Scott, D. O., Obach, R. S., et al. (2012). Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: Structure–activity relationships and discovery strategies to mitigate drug–drug interaction risks. J. Med. Chem. 55 (11), 4896–4933. doi:10.1021/jm300065h
Parsaee, F., Senarathna, M. C., Kannangara, P. B., Alexander, S. N., Arche, P. D. E., and Welin, E. R. (2021). Radical philicity and its role in selective organic transformations. Nat. Rev. Chem. 5 (7), 486–499. doi:10.1038/s41570-021-00284-3
Peng, F., Zhao, Q., Huang, W., Liu, S.-J., Zhong, Y.-J., Mao, Q., et al. (2019). Amine-catalyzed and functional group-controlled chemo- and regioselective synthesis of multi-functionalized CF3-benzene via a metal-free process. Green Chem. 21 (22), 6179–6186. doi:10.1039/C9GC02694K
Perkin, W. H. (1896). The origin of the coal-tar colour industry, and the contributions of Hofmann and his pupils. J. Chem. Soc. Trans. 69 (0), 596–637. doi:10.1039/CT8966900596
Pickford, H. D., Nugent, J., Owen, B., Mousseau, J. J., Smith, R. C., and Anderson, E. A. (2021). Twofold radical-based synthesis of N, C-difunctionalized bicyclo[1.1.1]pentanes. J. Am. Chem. Soc. 143 (26), 9729–9736. doi:10.1021/jacs.1c04180
Porta, R., Benaglia, M., and Puglisi, A. (2016). Flow chemistry: Recent developments in the synthesis of pharmaceutical products. Org. Process Res. Dev. 20 (1), 2–25. doi:10.1021/acs.oprd.5b00325
Quinn, R. A., Nothias, L. F., Vining, O., Meehan, M., Esquenazi, E., and Dorrestein, P. C. (2017). Molecular networking as a drug discovery, drug metabolism, and precision medicine strategy. Trends Pharmacol. Sci. 38 (2), 143–154. doi:10.1016/j.tips.2016.10.011
Rogers, L., and Jensen, K. F. (2019). Continuous manufacturing - the green chemistry promise? Green Chem. 21 (13), 3481–3498. doi:10.1039/c9gc00773c
Rosokha, S. V., and Kochi, J. K. (2008). Fresh look at electron-transfer mechanisms via the donor/acceptor bindings in the critical encounter complex. Acc. Chem. Res. 41 (5), 641–653. doi:10.1021/ar700256a
Semmler, K., Szeimies, G., and Belzner, J. (1985). Tetracyclo[5.1.0.01, 6.02, 7]octane, a [1.1.1]propellane derivative, and a new route to the parent hydrocarbon. J. Am. Chem. Soc. 107 (22), 6410–6411. doi:10.1021/ja00308a053
Shin, S., Lee, S., Choi, W., Kim, N., and Hong, S. (2021). Visible-light-induced 1, 3-aminopyridylation of [1.1.1]Propellane with N-aminopyridinium salts. Angew. Chem. Int. Ed. 60 (14), 7873–7879. doi:10.1002/anie.202016156
Simon, M. O., and Li, C. J. (2012). Green chemistry oriented organic synthesis in water. Chem. Soc. Rev. 41 (4), 1415–1427. doi:10.1039/c1cs15222j
Sodano, T. M., Combee, L. A., and Stephenson, C. R. J. (2020). Recent advances and outlook for the isosteric replacement of anilines. ACS Med. Chem. Lett. 11 (10), 1785–1788. doi:10.1021/acsmedchemlett.9b00687
Soto, F., Wang, J., Ahmed, R., and Demirci, U. (2020). Medical micro/nanorobots in precision medicine. Adv. Sci. (Weinh). 7 (21), 2002203. doi:10.1002/advs.202002203
Stepan, A. F., Subramanyam, C., Efremov, I. V., Dutra, J. K., O'Sullivan, T. J., DiRico, K. J., et al. (2012). Application of the bicyclo 1.1.1 pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active gamma-secretase inhibitor. J. Med. Chem. 55 (7), 3414–3424. doi:10.1021/jm300094u
Stepan, A. F., Walker, D. P., Bauman, J., Price, D. A., Baillie, T. A., Kalgutkar, A. S., et al. (2011). Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: A perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem. Res. Toxicol. 24 (9), 1345–1410. doi:10.1021/tx200168d
Sterling, A. J., Dürr, A. B., Smith, R. C., Anderson, E. A., and Duarte, F. (2020). Rationalizing the diverse reactivity of [1.1.1]propellane through σ–π-delocalization. Chem. Sci. 11 (19), 4895–4903. doi:10.1039/D0SC01386B
Studer, A., and Curran, D. P. (2016). Catalysis of radical reactions: A radical chemistry perspective. Angew. Chem. Int. Ed. 55 (1), 58–102. doi:10.1002/anie.201505090
Suarez, A. I. O., Lyaskovskyy, V., Reek, J. N. H., van der Vlugt, J. I., and de Bruin, B. (2013). Complexes with nitrogen-centered radical ligands: Classification, spectroscopic features, reactivity, and catalytic applications. Angew. Chem. Int. Ed. 52 (48), 12510–12529. doi:10.1002/anie.201301487
Sumida, Y., and Ohmiya, H. (2021). Direct excitation strategy for radical generation in organic synthesis. Chem. Soc. Rev. 50 (11), 6320–6332. doi:10.1039/d1cs00262g
Sun, G., Rong, D., Li, Z., Sun, G., Wu, F., Li, X., et al. (2021). Role of small molecule targeted compounds in cancer: Progress, opportunities, and challenges. Front. Cell Dev. Biol. 9, 694363. doi:10.3389/fcell.2021.694363
Walsh, J. S., and Miwa, G. T. (2011). Bioactivation of drugs: Risk and drug design. Annu. Rev. Pharmacol. Toxicol. 51 (1), 145–167. doi:10.1146/annurev-pharmtox-010510-100514
Wang, B., Peng, F., Huang, W., Zhou, J., Zhang, N., Sheng, J., et al. (2020). Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma. Acta Pharm. Sin. B 10 (8), 1492–1510. doi:10.1016/j.apsb.2019.12.013
Wegner, J., Ceylan, S., and Kirschning, A. (2012). Flow chemistry – a key enabling technology for (multistep) organic synthesis. Adv. Synth. Catal. 354 (1), 17–57. doi:10.1002/adsc.201100584
Westphal, M. V., Wolfstadter, B. T., Plancher, J. M., Gatfield, J., and Carreira, E. M. (2015). Evaluation of tert-butyl isosteres: Case studies of physicochemical and pharmacokinetic properties, efficacies, and activities. Chemmedchem 10 (3), 461–469. doi:10.1002/cmdc.201402502
Wiberg, K. B., and Waddell, S. T. (1990). Reactions of [1.1.1]propellane. J. Am. Chem. Soc. 112 (6), 2194–2216. doi:10.1021/ja00162a022
Wiberg, K. B., and Walker, F. H. (1982). [1.1.1]Propellane. J. Am. Chem. Soc. 104 (19), 5239–5240. doi:10.1021/ja00383a046
Wishart, D. S. (2016). Emerging applications of metabolomics in drug discovery and precision medicine. Nat. Rev. Drug Discov. 15 (7), 473–484. doi:10.1038/nrd.2016.32
Wong, M. L. J., Mousseau, J. J., Mansfield, S. J., and Anderson, E. A. (2019). Synthesis of enantioenriched α-chiral bicyclo[1.1.1]pentanes. Org. Lett. 21 (7), 2408–2411. doi:10.1021/acs.orglett.9b00691
Xiong, T., and Zhang, Q. (2016). New amination strategies based on nitrogen-centered radical chemistry. Chem. Soc. Rev. 45 (11), 3069–3087. doi:10.1039/c5cs00852b
Yang, X., Wang, Y. F., Byrne, R., Schneider, G., and Yang, S. Y. (2019). Concepts of artificial intelligence for computer-assisted drug discovery. Chem. Rev. 119 (18), 10520–10594. doi:10.1021/acs.chemrev.8b00728
Yu, X. Y., Zhao, Q. Q., Chen, J., Xiao, W. J., and Chen, J. R. (2020). When light meets nitrogen-centered radicals: From reagents to catalysts. Acc. Chem. Res. 53 (5), 1066–1083. doi:10.1021/acs.accounts.0c00090
Yu, Z., and Shi, L. (2022). Synthetic routes to bicyclo[1.1.1]pentylamines: Booming toolkits for drug design. Org. Chem. Front. 9 (13), 3591–3597. doi:10.1039/D2QO00703G
Zehnder, L., Bennett, M., Meng, J., Huang, B., Ninkovic, S., Wang, F., et al. (2011). Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-Amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2, 2-difluoropropyl)-5, 7-dihydro-6H-pyrrolo[3, 4-d] pyrimidine-6-carboxamide. J. Med. Chem. 54 (9), 3368–3385. doi:10.1021/jm200128m
Zehnder, L. R., Kung, P. P., Ninkovic, S., Meng, J. J., Huang, B., and Bennett, M. J. (2008). 2-amin0-5, 7-dihydr0-6H- pyrrolo [3, 4-d] pyrimidine derivatives as HSP-90 inhibitors for treating cancer. WO2008096218 (A1).
Zhang, X., Smith, R. T., Le, C., McCarver, S. J., Shireman, B. T., Carruthers, N. I., et al. (2020). Copper-mediated synthesis of drug-like bicyclopentanes. Nature 580 (7802), 220–226. doi:10.1038/s41586-020-2060-z
Zhao, Y., and Xia, W. (2018). Recent advances in radical-based C–N bond formation via photo-/electrochemistry. Chem. Soc. Rev. 47 (8), 2591–2608. doi:10.1039/C7CS00572E
Keywords: [1.1.1]propellane, bicyclo[1.1.1]pentylamine, radical chemistry, amination, bioisosteres
Citation: Pang Q, Li Y, Xie X, Tang J, Liu Q, Peng C, Li X and Han B (2022) The emerging role of radical chemistry in the amination transformation of highly strained [1.1.1]propellane: Bicyclo[1.1.1]pentylamine as bioisosteres of anilines. Front. Chem. 10:997944. doi: 10.3389/fchem.2022.997944
Received: 19 July 2022; Accepted: 10 October 2022;
Published: 21 October 2022.
Edited by:
Lucia Panzella, University of Naples Federico II, ItalyReviewed by:
Michal Szostak, Rutgers University, Newark, United StatesCopyright © 2022 Pang, Li, Xie, Tang, Liu, Peng, Li and Han. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xiang Li, lixiang2@cdutcm.edu.cn; Bo Han, hanbo@cdutcm.edu.cn
†These authors have contributed equally to this work and share first authorship